The long term goal of this proposal is to investigate the role of complement-derived anaphylatoxins, C3a and C5a, in regulation of human cell-mediated and humoral immunity. Preliminary studies indicate that C3a can suppress and C5a can enhance specific and nonspecific humoral immune responses. The proposed studies have been designed to ascertain the anaphylatoxin-cell and cell-cell interactions involved in anaphylatoxin-mediated regulation of the immune response. A comprehensive study will be conducted to define the cellular levels of C3a and C5a action. The requirement for accessory cells and the nature of signals provided by these cells will be extensively investigated. The fact that active synthetic peptides based on the C3a structure are known, will permit us to examine the active site of C3a as possible mediators of suppression. The possibility that anaphylatoxin-mediated immune regulation occurs through cytokine production will be examined. Studies on the regulation of the immune response by C3a and C5a will not only lead to a better understanding of lymphocyte activation, but also how complement components are involved in the cellular and subcellular events leading to immune regulation. These studies could lead to clinically valuable insight(s) such as how to use synthetic analogs or soluble factors derived from anaphylatoxin activated cells to modulate autoimmune diseases and as potential immunotherpeutic agents in cancer management.